Neural crest-specific loss of Bmp7 leads to midfacial hypoplasia, nasal airway obstruction and disordered breathing, modeling obstructive sleep apnea

Abstract

ABSTRACT Pediatric obstructive sleep apnea (OSA), a relatively common sleep-related breathing disorder affecting ∼1-5% of children, is often caused by anatomical obstruction and/or collapse of the nasal and/or pharyngeal airways. The resulting sleep disruption and intermittent hypoxia lead to various systemic morbidities. Predicting the development of OSA from craniofacial features alone is currently not possible, and controversy remains as to whether upper-airway obstruction facilitates reduced midfacial growth or vice versa. Currently, there is no rodent model that recapitulates both the development of craniofacial abnormalities and upper-airway obstruction to address these questions. Here, we describe that mice with a neural crest-specific deletion of Bmp7 (Bmp7ncko) present with a shorter, more acute-angled cranial base, midfacial hypoplasia, nasal septum deviation, turbinate swelling and branching defects, and nasal airway obstruction. Interestingly, several of these craniofacial features develop after birth during periods of rapid midfacial growth and precede the development of an upper-airway obstruction. We identified that, in this rodent model, no single feature appeared to predict upper-airway obstruction, but the sum of those features resulted in reduced breathing frequency, apneas and overall reduced oxygen consumption. Metabolomics analysis of serum from peripheral blood identified increased levels of hydroxyproline, a metabolite upregulated under hypoxic conditions. As this model recapitulates many features observed in OSA, it offers unique opportunities for studying how upper-airway obstruction affects breathing physiology and leads to systemic morbidities. This article has an associated First Person interview with the first author of the paper.